Destination Therapy: Given costs and complications, do we really want to go there? By Debra L. Beck

Jul 15, 2015

CardioSource WorldNews

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Cover Story | “There has been tremendous progress made in mechanical circulatory support over the past decade,” said G. William Dec, MD, FACC, from Massachusetts General Hospital, Boston, MA, “and I think that we are almost at the cusp of when we are going to be offering our patients an LVAD as opposed to a transplant as primary therapy.”

And in a JACC State-of-the-Art review on LVADs from June 2015,1 Donna Mancini, MD, and Paolo C. Colombo, MD, FACC (both from Columbia University, New York, NY), noted that, while the 2013 International Society of Heart Lung Transplant (ISHLT) mechanical devices guidelines recommend first asking whether the patient is a candidate for a heart transplant, this may soon change. They wrote, “With the rapid advances in mechanical circulatory support, this algorithm may be revised in the near future such that the initial question is eligibility for destination therapy (DT), followed by heart transplantation candidacy and palliation.”

Where We’re Headed: Destination LVAD

Use of an LVAD for DT (i.e., the LVAD is the only option, not a bridge to anywhere) currently is indicated for patients with New York Heart Association (NYHA) class IV end-stage ventricular heart failure (HF) who are not candidates for heart transplant and, according to the Centers for Medicare & Medicaid Services,2 meet all of the following conditions:

Have failed to respond to optimal medical management (including beta-blockers and angiotensin-converting enzyme inhibitors if tolerated) for at least 45 of the last 60 days, or have been balloon pump dependent for 7 days, or intravenous (IV) inotrope dependent for 14 days;

Have an LV ejection fraction (LVEF) <25%; and

Have demonstrated functional limitation with a peak oxygen consumption of ≤14 ml/kg/min unless balloon pump or inotrope dependent or physically unable to perform the test.

Mechanical circulatory support (MCS) as DT constitutes a large and growing proportion of overall implants. In the United States, the percentage of patients receiving a durable device as DT has increased from 14.7% in 2006-2007 (n = 64) to 19.6% in 2008-2010 (n = 666) to 41.6% in 2011-2013 (n = 2,781).3 Similarly, the proportion of patients actually listed for cardiac transplant at the time of implant has decreased from 42.4% (2006-2007) to 21.7% (2011-2013).3

Continuous-flow (CF) pumps have accounted for virtually 100% of devices in patients receiving DT since 2010 and actuarial survival is currently 81% at 1 year, 70% at 2 years, 60% at 3 years, and 48% at 4 years.

“It is estimated that, by 2015-16, about 60% of all LVADs implanted will be for permanent support,” said Dr. Dec.

Complications Shift

Heart transplantation continues to provide the best possible outcomes for patients with advanced HF, noted Dr. Dec at ACC.15. Current survival rates after transplantation are about 75% at 5 years and 60% at 10 years.4 He added that some of the best programs have 10-year survival rates “pushing 80%.”

But transplantation continues to be limited by a lack of organs. Only about 2,400 individuals in North America receive heart transplants annually—and this has held fairly steady for the last couple decades—even though two to three times that number of people are listed for transplant each year.

Randall C. Starling, MD, MPH, FACC, is the medical director of the Kaufman Center for Heart Failure at the Cleveland Clinic. He noted in JACC that improvements in quality of life (QOL) measures and functional capacity with CF pumps as DT are “unparalleled.”5 With 80% of patients improving to NYHA class I or II after LVAD implantation, he wrote, “It appears that improved survival with LVAD compared with medical therapy was not enough to convince clinicians and patients to accept LVAD therapy in the past. Now, however, the combination of improved survival and improved QOL has resulted in wide acceptance of continuous-flow LVAD and rapid growth in their use.”

Although adverse events occur frequently (TABLE), their rates have been substantially reduced since the early pulsatile-pump days. Having said that, over a 6-year period, there has been a reduction in some adverse events but an increase in others. Consequently, there has been only a slight reduction in total burden of adverse events over that time period.3

In the post-approval HM II DT study, the reported rates at 2 years were driveline infection in 19%, sepsis in 19%, stroke in 11.7%, thrombus formation in 3.6%, bleeding in 54%, mechanical failure requiring replacement in 4%, and right HF in 18%. It’s the last event—right-sided HF—that is the most feared event, said Dr. Dec, although there are selection criteria aimed at avoiding it.

In early 2014, reports emerged of markedly increased pump thrombosis incidence since 2011.6,7 These reports received a lot of attention, in part because it looked like a huge chink in the LVAD armor. Of note, higher rates were reported for both devices (HeartMate and HeartWare) commercially available in the United States.6,8

Efforts to understand the sudden increase in pump thrombosis led most to conclude that the causes are multifactorial and likely related to the rapid adoption of LVADs for DT since 2010. In their recent review, Mancini and Colombo listed the possible causes: “Less frequent use of perioperative heparin use, lower target INR ranges due to the high incidence of bleeding, inadequate antiplatelet therapy, overestimate of effective anticoagulation by the partial prothrombin time, abnormal angulation of inflow or outflow cannulas, infection, use of erythropoeietic factors, and/or other factors not yet identified.”

“The noise level seems to be somewhat down in the thrombus issue,” said Thoratec CEO Keith Grossman in a quarterly (Q3) 2014 earnings call, but it adds to the overall adverse event issue. “The discussion that I’m hearing is no longer really about one specific type of adverse event, with one pump, but adverse events generally speaking and where we are now and where we should be as an industry.”

Another adverse event relates to the deleterious cognitive effects of LVADs. Timothy Fendler, MD, Saint Luke’s Mid America Heart Institute, Kansas City, MO, and colleagues just reported using the Interagency Registry for Mechanically Assisted Circulatory Support to evaluate cognitive function in nearly 1,200 patients who underwent LVAD implantation.9 The cumulative incidence of cognitive decline in the year after LVAD implantation was 29.2%. In adjusted analysis, older age (≥70 versus <50 years; hazard ratio, 2.24) and destination therapy (hazard ratio, 1.42) were significantly associated with greater risk of cognitive decline. The possible mechanism: major, minor, and mini strokes that occur due to blood clots caused by the device.

Interestingly, cognition often improved for those patients without cognitive decline, supporting the notion that LVADs improve cerebral perfusion, unless a patient experiences an ischemic event, which is a big if given that these events occur commonly. Brahmajee Nallamothu, MD, MPH, chair of Quality of Care and Outcomes Research for the American Heart Association, said, “We need to understand these complications if we’re going to start broadening their use.” However, he noted that Dr. Fendler’s research only showed an association—not a proven link—between LVADs and mental decline in some patients.

“These are really sick patients, and they have a lot of reasons to suffer cognitive decline,” said Dr. Nallamothu. “These are people who otherwise without the device in all likelihood would die within a short time period. That’s a real key point.”

A second new study, this one much smaller, looked at 176 LVAD patients who were tested using the MoCA (Montreal Cognitive Assessment), a simple screening tool sensitive to mild cognitive impairment. Pre-LVAD implantation, cognitive impairment was seen in 67% of the study cohort. In the 56 patients re-evaluated at 8 months post-implantation, total MoCA score as well as the visuospacial, executive, and delayed recall cognitive domains were significantly improved as a group.10

Another notable adverse event after implantation of a continuous-flow LVAD is gastrointestinal bleeding (GIB). In an abstract presented at Heart Failure 2015, researchers at the University of Texas Health Science Center, Houston, TX, showed that GIBs occur in about 24% of patients receiving CF-LVADs, with no difference in incidence in regard to device type, INTERMACS score, or blood types.11 On regression analysis, the only significant risk factor for GIB was the presence of chronic kidney disease, giving clinicians little information for preventing this adverse event or its recurrence.

Continual Technological Evolution

There are currently two U.S. Food and Drug Administration (FDA)-approved MCS devices for adults: The HeartMate II (Thoratec Corporation, Pleasanton, California) CF pump (IMAGE 1) was approved for bridge-to-transplant therapy (BTT) in 2008 and for DT in 2010. The HeartWare HVAD (HeartWare International, Inc., Framingham, MA; the H stands for HeartWare) was approved for BTT in November 2012. (One pediatric device has also been approved: the MicroMed DeBakey Child ventricular assist device.)

Three more second-generation devices—the Jarvik 2000 (Jarvik Heart), Incor (Berlin Heart), and HeartAssist 5 (ReliantHeart)—are commercially available in Europe but investigational in the U.S.

In April 2015, Thoratec Corporation announced approval from the FDA to broaden enrollment of its HeartMate III U.S. investigational device exemption trial to as many as 60 sites across the U.S. from the initial limited enrollment phase of five sites.

The expanded pivotal trial is evaluating the third-generation Thoratec LVAD which utilizes a fully magnetically levitated rotor (“bearingless”) technology. Avoiding hydrodynamic bearings may reduce thrombus risk and pump dysfunction. The design also differs from second-generation devices in that it allows for gaps in the blood flow that are 10 to 20 times wider, which are meant to minimize blood component trauma. The shear force characteristics of current devices cause damage to red blood cells and von Willebrand factor, plus they activate platelets.

The first 294 randomized patients in the HeartMate III U.S. clinical trial will be followed for 6 months to evaluate short-term use (such as BTT) and 366 randomized patients will be followed for 24 months to evaluate long-term use (such as DT), comparing HM III to HM II in a noninferiority design. The trial allows for about 600 additional patients to be enrolled beyond the pivotal cohort in order to assess superiority of pre-specified secondary endpoints.

The HeartMate III CE Mark study finished enrollment in late 2014 and commercial approval and launch in European markets could occur as soon as late 2015.

The MVAD represents the next generation HeartWare device. The M stands for miniature and, indeed, this continuous axial flow pump is about one third the size of the second-generation HVAD (IMAGE 2). For comparison, the first-generation Thoratec VAD was pneumatic (air-driven) and weighed 570 grams. The HeartMate III LVAD under study is magnetic and weighs in at 200 grams while the HeartWare MVAD is hydrodynamic and is just 92 grams.

In collaboration with Dualis Medtech GmbH, a company spun out of the German Centre for Aeronautics and Aerospace research organization, HeartWare is also developing fully implantable electronics systems based on transcutaneous energy transfer (TET) technology that will enable the implanted battery pack to be periodically recharged using inductive coupling across the skin, eliminating the need for a percutaneous driveline to connect to a permanent controller. The company hopes this will improve the adverse event profile and extend the device longevity as well as improve QOL.

Dr. Starling expects that LVADs will continue to evolve and improve, with devices that will likely be totally implanted, smaller, and lighter, and with a reduced risk of adverse events. Eventually, these devices may be used in patients who are less ill, meaning expanded use in the future.

Benching the Heart

The possibility that LVADs may allow an overworked and ailing native heart to recover near-normal function is exciting and, some think, the future of the field.

LVADs provide marked pressure and volume unloading of the left ventricle, resulting in notable reductions in ventricular size and shape, followed by structural, biochemical, and genetic changes. This phenomenon of reverse remodeling was noted early on by clinicians who saw that upon removing the LVADs of some patients to perform a heart transplant, the failed hearts appeared much improved.

A strategy was developed at Harefield Hospital (Harefield, Middlesex, United Kingdom) that combined LVAD mechanical unloading with pharmacological intervention to maximize myocardial recovery. The group, led by Emma Birks, MD, PhD, reported phenomenal success in patients with severe HF of nonischemic etiology: using the continuous-flow HM II device, 60% of patients showed sufficient recovery to meet explantation criteria.12 Actuarial survival after explantation was 83.3% at both 1 and 3 years. Unfortunately, a U.S. version of the study did not replicate these results and most U.S. reports have shown recover rates <10%.

Restaging HF

These days, Dr. Birks is the director of the Jewish Hospital Heart Failure, Transplant and Mechanical Support Program at the University of Louisville, KY, and the principal investigator of the ongoing Remission from Stage D Heart Failure (RESTAGE-HF) trial.

RESTAGE-HF is a multicenter prospective study that combines prolonged optimized mechanical unloading with the HM II together with a standardized protocol of specific pharmacological therapies designed to induce profound reverse structural remodeling and reduce fibrosis. A testing protocol where the LVAD speed is turned down and the native heart function assessed by echocardiogram is used to determine whether the LVAD can be removed within 18 months.

Early results presented by Dr. Birks in April at the 2015 annual scientific sessions of the ISHLT in Nice, France, showed that five of the surviving 20 LVAD recipients have met pre-defined criteria and have successfully been explanted after a support duration of 265 days.13 The median age of those explanted was 45 years and median duration post explant is 138 days to date.

At implant (n = 22), 61% of the patients were INTERMACS 1 or 2 and 39% were INTERMACS 3 or 4. About half (48%) had a 1-5-year HF duration, 33% had an HF history of 3-6 months, and 19% <3 months.

The pharmacological treatment intended to enhance reverse remodeling includes drugs initiated immediately after weaning of inotropic support once achieving adequate end-organ recovery and titrated (against symptoms, potassium, and renal function) to maximal doses.

Along with novel strategies, like clenbuterol (a decongestant and bronchodilator not currently available in the U.S.), stem cell and gene therapies might be combined with myocardial recovery protocols to help LVAD-supported hearts recover enough function to tolerate weaning and eliminate or reduce the need for transplantation. Now there’s a destination!

The National Institutes of Health is starting a trial that will use stem cells at the time of LVAD implantation. Leslie W. Miller, MD, told CardioSource WorldNews. “The stability of the LVAD make it the ideal platform to examine the potential benefit of stem cell and/or gene therapy as adjuncts, especially with new protocols designed for repeat administrations.” Dr. Miller is one of the editors of Mechanical Circulatory Support, A Companion to Braunwald’s Heart Disease.

Cost of the LVAD Road Trip

The future of LVADs as substitutes for heart transplantation brings with it the obvious question of cost, particularly as the devices start to be used in less sick patients. (Limiting the population to current guidelines, estimates of the number of potential LVAD recipients in the United States range from about 250,000 to 300,000.)

At current costs, LVADs easily blow past the <$100,000 USD/QALY that is generally considered more or less cost-effective therapy.14 (A “desirable” cost would be <$20,000, which isn’t going to happen any time soon with LVADs.) The cost effectiveness of LVAD therapy as DT is improving and refinements in patient selection and management should have a favorable impact on the total cost of this therapy.14

As for moving this therapy into a lower-risk population, ROADMAP (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients) is a nonrandomized study sponsored by Thoratec that enrolled 200 ambulatory patients with NYHA functional class IIIb to IV HF not on parenteral inotropic therapy, with LVEF ≤25% and a 6-minute walk distance <300 meters. Median age was 65 years and almost three-quarters were male.

ROADMAP presented initial findings at ISHLT 2015, showing that at 1 year 39% of patients were alive and increased their walk distance by 75 meters, compared with 21% of patients on optimal medical management (p = 0.017).15 QOL scores were also much improved in the device arm.

Within the LVAD group, 77% of patients improved to NYHA class I or II status compared with only 29% in NYHA class II and no class I patients in the optimal medical management group. Also, postoperative mortality after LVAD implantation was 1%, the lowest seen yet in a trial, and equivalent to the 30-day mortality seen in the optimal medical group.

Unfortunately, adverse events rates in ROADMAP were not improved from those seen in the original pivotal HMII DT clinical trial, with bleeding being the most frequent adverse event, seen in 47% (31% with GIB). Pump thrombosis was seen in 6.4% of patients and stroke in 9.6%. Overall, the composite event rate was 66%, or 1.89 events per patient per year, as compared to 2.09 events per patient per year in the DT trial.

ROADMAP results support the use of LVADs in functionally limited non-inotrope dependent HF patients but it was a nonrandomized study and should be considered only hypothesis generating, noted Drs. Mancini and Colombo. Dr. Miller said that the ROADMAP cost data should be reported soon and will be an important update to consider.

As Dr. Dec pointed out, at $150,000 in costs for implantation and the first year of care, the price tag is about the same as heart transplantation; if LVADs want to play to a larger audience, the devices need to become smaller, lighter, totally implantable, more durable, less costly, reliable for biventricular support, and associated with lower rates of stroke and infection.

“If these things happen, transplant may be used in the future as a salvage for complications and for those who are not eligible for mechanical circulatory support, rather than the other way around,” he said.